ECG-based markers of autonomic neuropathy as predictors of cardiovascular disease in type 1 diabetes

Aims: To evaluate the impact of cardiovascular autonomic neuropathy (CAN) on cardiovascular disease (CVD) in adults with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications (EDIC) study.

Methods: Data from 997 participants with ECG-derived CAN data available at EDIC year 22 (2015) and follow-up data collected through EDIC year 29 (2022) were analysed, while ECGs showing arrhythmias, conduction defects, or more than 50% ectopic beats were excluded. Previously validated ECG-derived CAN measures were derived: the standard deviation of normally conducted R-R intervals (SDNN) and the root mean square of successive differences between normal-to-normal R-R intervals (rMSSD). ECG-derived CAN was analysed for its association with risk factors and its impact on CVD and major atherosclerotic cardiovascular events (MACE) using general estimating equation models (GEE), Kaplan-Meier, and Cox regression models.

Results: The average prevalence of ECG-derived CAN was 64% across the 7 years of the study, and on average it was lower in the group that had received intensive treatment during the DCCT. In the GEE model, higher mean pulse rate was the most significant risk factor for the development of ECG-derived CAN, followed by higher HbA1c, older age, male sex, higher albumin excretion rate, and hypertension. The incidence of any CVD and of MACE was significantly higher in participants with ECG-derived CAN compared to those without. This finding remained significant after adjustment for HbA1c and age, but not when further adjusted for risk factors for CVD identified during the DCCT.

Conclusions: The reported prevalence of ECG-derived CAN was similar to previously reported estimates using cardiovascular autonomic reflex tests. CVD risk was significantly higher in those with versus without CAN.

Comments: CAN is a common complication in diabetes and a predictor of CVD and mortality. Despite this, CAN is rarely investigated in current clinical practice, mostly due to the limited feasibility of assessing CAN using the gold-standard cardiovascular autonomic reflex tests, which can be time consuming and expensive. This study highlights the potential utility of determining heart rate variability obtained using standard ECGs as a surrogate measure for CAN. The group has previously demonstrated agreement between indices of ECG-derived CAN and the gold-standard test. This study further highlights the utility of this method by demonstrating that ECG-derived CAN measures identify people at higher risk of developing CVD. Thus, using a simple and common bedside test, these surrogate markers could potentially be used to stratify those at higher risk of future CVD. Future work to determine specific thresholds to diagnose ECG-derived CAN, and studies in other populations, are warranted to confirm these findings before integration into clinical practice.

Gordon Sloan

Reference: Braffett BH, El Ghormli L, Martin C, White NH, Hirsch IB, Bantle A, Carlson A, Leschek E, Gubitosi-Klug R, Soliman EZ, Vella A, Perkins BA, Bebu I, Pop-Busui R; DCCT/EDIC Research Group. Cardiovascular autonomic neuropathy defined by indices of heart rate variability is associated with cardiovascular disease: a longitudinal cohort study of participants with type 1 diabetes. Cardiovasc Diabetol. 2025 Aug 13;24(1):334. doi: 10.1186/s12933-025-02856-9. PMID: 40804720; PMCID: PMC12351983.

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